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Gene Review

Kcnd2  -  potassium voltage-gated channel, Shal...

Mus musculus

Synonyms: AI839615, AW555701, Kiaa1044, Kv4.2, MNCb-7013, ...
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Disease relevance of Kcnd2

  • Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction [1].
  • KChIP2, a gene encoding three auxiliary subunits of Kv4.2 and Kv4.3, is preferentially expressed in the adult heart, and its expression is downregulated in cardiac hypertrophy [2].
  • Studies with chick cochlear tissues reveal that Kv4.2 coprecipitates PPTX and that both proteins are colocalized to the sensory and ganglion cells [3].
  • Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic [4].
  • Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates [5].

High impact information on Kcnd2

  • We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased Kv4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I(to,f), and increased susceptibility to arrhythmias [6].
  • Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons [5].
  • Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors [5].
  • These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity [5].
  • Further studies of a TopIIbeta-sensitive gene, Kcnd2, revealed the presence of TopIIbeta in the transcription unit with major binding near the promoter region [7].

Chemical compound and disease context of Kcnd2


Biological context of Kcnd2

  • Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain [9].
  • In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I(to,f) in Kv4.2(-/-) mice does not result in ventricular hypertrophy [1].
  • TLTx1 inhibited Kv4.2-mediated currents with an IC50 of approximately 200 nM, and macroscopic current inactivation was slowed in the presence of TLTx1 [10].
  • TLTx1 caused a noticable slowing of Kv4.2 activation kinetics, and Kv4.2 deactivation kinetics were accelerated by TLTx1 as infered from Rb+ tail current measurements [10].
  • A point mutation (W to F) was introduced at position 362 in the pore region of Kv4.2 to produce a nonconducting mutant (Kv4.2W362F) subunit [11].

Anatomical context of Kcnd2

  • Unexpectedly, voltage-clamp recordings from Kv4.2(-/-) ventricular myocytes revealed that I(to,f) is eliminated [1].
  • In all layers, clusters of Kv4.2 and Kv4.3 immunoreactivity are evident in the membranes of the somata, dendrites, and spines of pyramidal cells and GABAergic interneurons [12].
  • Electron microscopic analyses revealed that Kv4.2 and Kv4.3 clusters in pyramidal cells and interneurons are excluded from putative excitatory synapses, whereas postsynaptic membranes at GABAergic synapses often contain Kv4.2 and Kv4 [12].
  • Here, we used immunolabeling with specific antibodies against Kv4.2 and Kv4.3, in combination with GABA immunogold staining, to determine the cellular, subcellular, and synaptic localization of Kv4 channels in the primary visual cortex of mice, in which subsets of pyramidal cells express yellow fluorescent protein [12].
  • Together our data show that Kif17 is probably the motor that transports Kv4.2 to dendrites but suggest that this motor does not, by itself, specify dendritic localization of the channel [13].

Associations of Kcnd2 with chemical compounds

  • Flecainide (10 microM) had minimal effects on Kv1.4 currents, but reduced Kv4.2 peak current by 53% and increased the apparent rate of inactivation consistent with open channel block [14].
  • Activation of NMDA- and/or AMPA-type glutamate receptors was necessary for the targeting of Kv4.2 in co-cultures, and activation of these receptor systems in GC monocultures induced dendritic targeting of Kv4.2 in the absence of synapse formation [15].
  • High-resolution confocal microscopy revealed that there was no apparent association between Kv4.2-positive puncta with major synaptic markers, such as vesicular glutamate transporters and glutamic acid decarboxylase [16].

Physical interactions of Kcnd2


Enzymatic interactions of Kcnd2


Co-localisations of Kcnd2


Regulatory relationships of Kcnd2

  • In addition, the slow transient outward K+ current, I(to,s), and the Kv1.4 protein (which encodes I(to,s)) are upregulated in Kv4.2(-/-) ventricles [1].
  • Both A-type currents in cultured hippocampal neurons and A-type currents recorded from HEK 293 cells transiently expressing recombinant Kv4.2 channels were selectively inhibited by T. leblondi venom [10].
  • We show that a dominant negative construct against Kif17 dramatically inhibits localization to dendrites of both introduced and endogenous Kv4.2, but those against other kinesins found in dendrites do not [13].

Other interactions of Kcnd2

  • Similar to Kv4.3, expression of Kvbeta1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2(-/-) ventricles [1].
  • Immunoblot and immunohistochemical studies confirmed the existence of Kv1.4 and Kv4.2/3 subunits [18].
  • Recently, a mouse was generated with a targeted deletion of Kv4.2, a Kv4 alpha subunit expressed in many but not all mammalian brain neurons [9].
  • The impact of Kv4.2 deletion on KChIP expression also supports the major role of KChIPs as auxiliary subunits of Kv4 channels [9].
  • Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2(-/-) ventricles [1].

Analytical, diagnostic and therapeutic context of Kcnd2


  1. Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Guo, W., Jung, W.E., Marionneau, C., Aimond, F., Xu, H., Yamada, K.A., Schwarz, T.L., Demolombe, S., Nerbonne, J.M. Circ. Res. (2005) [Pubmed]
  2. A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Kuo, H.C., Cheng, C.F., Clark, R.B., Lin, J.J., Lin, J.L., Hoshijima, M., Nguyêñ-Trân, V.T., Gu, Y., Ikeda, Y., Chu, P.H., Ross, J., Giles, W.R., Chien, K.R. Cell (2001) [Pubmed]
  3. A secretory-type protein, containing a pentraxin domain, interacts with an A-type K+ channel. Duzhyy, D., Harvey, M., Sokolowski, B. J. Biol. Chem. (2005) [Pubmed]
  4. Characterization of mice with a combined suppression of I(to) and I(K,slow). Brunner, M., Guo, W., Mitchell, G.F., Buckett, P.D., Nerbonne, J.M., Koren, G. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  5. The kv4.2 potassium channel subunit is required for pain plasticity. Hu, H.J., Carrasquillo, Y., Karim, F., Jung, W.E., Nerbonne, J.M., Schwarz, T.L., Gereau, R.W. Neuron (2006) [Pubmed]
  6. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Costantini, D.L., Arruda, E.P., Agarwal, P., Kim, K.H., Zhu, Y., Zhu, W., Lebel, M., Cheng, C.W., Park, C.Y., Pierce, S.A., Guerchicoff, A., Pollevick, G.D., Chan, T.Y., Kabir, M.G., Cheng, S.H., Husain, M., Antzelevitch, C., Srivastava, D., Gross, G.J., Hui, C.C., Backx, P.H., Bruneau, B.G. Cell (2005) [Pubmed]
  7. Role of Topoisomerase II{beta} in the Expression of Developmentally Regulated Genes. Lyu, Y.L., Lin, C.P., Azarova, A.M., Cai, L., Wang, J.C., Liu, L.F. Mol. Cell. Biol. (2006) [Pubmed]
  8. Calcineurin Increases Cardiac Transient Outward K+ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits. Gong, N., Bodi, I., Zobel, C., Schwartz, A., Molkentin, J.D., Backx, P.H. J. Biol. Chem. (2006) [Pubmed]
  9. Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain. Menegola, M., Trimmer, J.S. J. Neurosci. (2006) [Pubmed]
  10. Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi. Ebbinghaus, J., Legros, C., Nolting, A., Guette, C., Celerier, M.L., Pongs, O., Bähring, R. Toxicon (2004) [Pubmed]
  11. Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. Barry, D.M., Xu, H., Schuessler, R.B., Nerbonne, J.M. Circ. Res. (1998) [Pubmed]
  12. Differential Expression of IA Channel Subunits Kv4.2 and Kv4.3 in Mouse Visual Cortical Neurons and Synapses. Burkhalter, A., Gonchar, Y., Mellor, R.L., Nerbonne, J.M. J. Neurosci. (2006) [Pubmed]
  13. A role for Kif17 in transport of Kv4.2. Chu, P.J., Rivera, J.F., Arnold, D.B. J. Biol. Chem. (2006) [Pubmed]
  14. Electrophysiological and pharmacological correspondence between Kv4.2 current and rat cardiac transient outward current. Yeola, S.W., Snyders, D.J. Cardiovasc. Res. (1997) [Pubmed]
  15. Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons. Shibasaki, K., Nakahira, K., Trimmer, J.S., Shibata, R., Akita, M., Watanabe, S., Ikenaka, K. J. Neurochem. (2004) [Pubmed]
  16. Postsynaptic and extrasynaptic localization of Kv4.2 channels in the mouse hippocampal region, with special reference to targeted clustering at gabaergic synapses. Jinno, S., Jeromin, A., Kosaka, T. Neuroscience (2005) [Pubmed]
  17. Input-specific immunolocalization of differentially phosphorylated Kv4.2 in the mouse brain. Varga, A.W., Anderson, A.E., Adams, J.P., Vogel, H., Sweatt, J.D. Learn. Mem. (2000) [Pubmed]
  18. Pituitary adenylate cyclase activating polypeptide reduces expression of Kv1.4 and Kv4.2 subunits underlying A-type K(+) current in adult mouse olfactory neuroepithelia. Han, P., Lucero, M.T. Neuroscience (2006) [Pubmed]
  19. Role of heteromultimers in the generation of myocardial transient outward K+ currents. Guo, W., Li, H., Aimond, F., Johns, D.C., Rhodes, K.J., Trimmer, J.S., Nerbonne, J.M. Circ. Res. (2002) [Pubmed]
  20. Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression. Spreafico, F., Barski, J.J., Farina, C., Meyer, M. Mol. Cell. Neurosci. (2001) [Pubmed]
  21. Characterization of the A-type potassium current in murine gastric antrum. Amberg, G.C., Baker, S.A., Koh, S.D., Hatton, W.J., Murray, K.J., Horowitz, B., Sanders, K.M. J. Physiol. (Lond.) (2002) [Pubmed]
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